Oral formulations of diaminophenothiazines and methods of making and using same in treatment and / or prophylaxis of disease

Abstract

Disclosed is an oral formulation comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform, as well as its veterinary use in the treatment and / or prevention of a disease, such as an avian depletion disease. Methods of treating and / or preventing a disease, such as an avian depletion disease, by administering to an animal suffering from the disease, such as an avian depletion disease, an effective amount of a diaminophenothiazine compound in an oral formulation having a mucoadhesive gastric retention platform. The treated birds can recover from diseases which cannot be treated previously.

Description

Citation of Related Applications

[0001] This application claims priority to Singapore patent application number 10202251102T filed on September 21, 2022, the contents of which are incorporated herein by reference. Technical Field

[0002] The present disclosure generally relates to oral formulations of diaminophenothiazines for use in medicine, and their use in the treatment and / or or methods of preparation and use in the prevention of veterinary diseases, particularly diseases in birds. Background Art

[0003] The following discussion of the background of the present invention is intended only to facilitate understanding of the present invention. It should be understood that The discussion is not an acknowledgement or admission that any of the material referred to was published, known or part of the common general knowledge of the skilled person in any jurisdiction as at the priority date of the present invention.

[0004] Birds live and breed in most terrestrial habitats on all continents of the Earth. Many species migrate long distances each year. These common long-distance flights increase the spread of avian diseases. In addition to the common spread caused by migration, infections in birds occur particularly in closed breeding environments. These infections can spread rapidly among the many birds that reside in aviaries for breeding purposes, causing significant avian morbidity and mortality through wasting. Wasting disease can be caused by enteric peripheral neuropathy, in which the peripheral nerves in the avian pronephros-gastrointestinal tract become dysfunctional. Due to the neuropathy, the motility and secretory functions of the gastrointestinal system can be impaired, ultimately leading to nutrient malabsorption, starvation, wasting, and death. Perforation of gastrointestinal structures can occur due to severe distension caused by ingested food particles becoming stagnant and accumulating in the gastrointestinal tract. Enteric peripheral neuropathy can even lead to central nervous system dysfunction through the gut-brain axis, ultimately affecting the brain. Three of the most common avian infections that can lead to such severe consequences include: Avian Megalobacteriosis, Avian Bornavirusinfection and Parrot beak and feather disease. Other avian wasting diseases, such as avian Borna virus, can cause other serious symptoms of the brain in addition to wasting disease because the virus is able to travel through the nervous system via the peripheral nerve plexus of the gastrointestinal tract. For most avian diseases, a preventive measure to prevent the spread of infection is to cull entire flocks of birds living in the same enclosure. This approach is cruel and expensive when only a few infected birds are found.

[0005] Avian Megalobacteriosis or Avian Gastric Yeast is caused by the fungus Macrorhabdus ornithogaster. Common reported symptoms of illness include chronic weight loss, apathy, anorexia, vomiting / Regurgitation and passage of whole or partial seeds in soft, watery stools. Digested blood may also be seen in the stools. In advanced stages of the disease, vomiting of thick material may occur. Chronic wasting occurs over a long period of time. The course of the disease may be several months with intermittent recovery and relapse. Due to its size, the giant bacterium is easily recognized under the microscope and can be diagnosed by wet mounts or stained smears from crop swabs, forestomach scrapings, and stool. Radiographs may show a dilated forestomach and an hourglass-shaped constriction between the forestomach and gizzard. By contrast (barium) Examination may also reveal thickening of the anterior gastric wall.

[0006] Elimination of avian megabacterial disease can be difficult because there are currently no known effective treatments or preventive measures. Megabacteria have proven resistant to tested antibiotics. Furthermore, control of the disease has not been adequately described. Some treatment options described as having some promise attempt to lower the pH of the forestomach (usually using lactic acid bacteria) to reverse the effects of the disease and make the environment less favorable for megabacterial survival. In some cases of megabacterial disease, as well as in cases of enteritis that do not respond to conventional treatments, acidification of drinking water with hydrochloric acid may help. Use of the antifungal drug amphotericin B has been observed. There have been some successful cases of amphotericin B use, however, oral formulations of amphotericin B can be difficult to obtain.

[0007] Avian bornaviral ganglioneuritis, commonly known as parrot wasting disease, is presumed to be caused by a recently discovered strain of the Bornavirus family. or avian borna virus (ABV). Research into the pathogenesis and treatment of the disease is ongoing. Currently, there are no best practices for transmission, diagnostic sampling and testing, and There are still many unanswered questions about whether currently used drug therapies are effective or harmful to sick birds. Avian Borna virus is an opportunistic virus that also primarily causes forestomach dilatation disease (PDD) in parrots. PDD is a fatal inflammatory disease of birds in the forestomach of the upper gastrointestinal tract.

[0008] Psittacine beak and feather disease (PBFD), also known as parrot beak and feather disease, psittacine circovirus (PCV) or psittacine circoviral disease (PCD). It is the most common and highly contagious viral disease in parrots and related species, caused by psittacine circovirus. Circovirus infection has been reported in at least 18 wild and domestic non-psittacine birds, including Columbiformes, Passeriformes, Anseriformes, Galliformes, Charadriiformes and Struthionidae, including pigeons, finch, canary, goose, duck, pheasant, seagull and ostrich. The disease occurs in acute fatal and chronic forms. The disease manifests as an immunosuppressive state, with irreversible feather loss, beak and claw deformities, and ultimately leads to death, which is usually secondary infection caused by decreased immunity. Common diagnostic methods include histology, PCR, or various antibody techniques (including ELISA). Currently, there is no commercially available specific treatment for birds with chronic PBFD. Detection and culling of infected birds is often performed as a means of preventing further spread of the disease within infected captive or commercial flocks. There is an ongoing need to develop a vaccine or treatment or preventive method to combat BFDV infection.

[0009] Diaminophenothiazine (DAPTZ) compounds, such as methylene blue, have been shown to be helpful in treating a variety of human microbial infections, including vaginal candidiasis, hepatitis C, and malaria.

[0010] Non-isocyanate diaminophenothiazine compounds (reduced and oxidized forms, after H2+HCl oxidation) A limiting example is shown below:

[0011] Reduction form

[0012] Oxidized form (MTC)

[0013] For example, the oxidized and reduced forms of DAPTZ compounds include, but are not limited to, methylthioninium chloride (MTC). MTC produces two different forms of active methylthioninium (MT) moieties, namely, a positively charged oxidized form and a neutrally charged reduced (colorless) form of the MT moiety. The MT moiety is the active moiety, which is absorbed through the stomach and intestines to enter the blood. It should be understood that the positively charged oxidized MT form is blue compared to the colorless, neutrally charged reduced form, which has no color. Therefore, the two forms are visually distinct. DAPTZ compounds are typically administered as a drug for the treatment of methemoglobinemia. DAPTZ compounds are typically injected intravenously because oral formulations have a short duration of action.

[0014] There is a need to provide methods for treating and / or preventing diseases such as avian wasting disease, and / or to alleviate at least one of the above-mentioned problems. Summary of the invention

[0015] An oral formulation for the treatment and / or prevention of a disease, such as avian wasting disease, is contemplated. It has sustained / controlled release or is targeted to the upper gastrointestinal tract.

[0016] Accordingly, one aspect of the present invention relates to an oral formulation comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC), the oral formulation being for veterinary use in the treatment and / or prevention of a disease.

[0017] According to another aspect of the present invention, it relates to an oral formulation comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform, wherein the oral formulation is used for veterinary use in treating and / or preventing diseases associated with intestinal peripheral neuropathy.

[0018] According to another aspect of the present invention, it relates to an oral formulation comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform for veterinary use in the treatment and / or prevention of avian wasting disease.

[0019] According to another aspect of the present invention, it relates to an oral formulation comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform for veterinary use in the treatment and / or prevention of esophageal-gastric perforation or ulceration of the upper gastrointestinal tract caused by an infectious agent.

[0020] According to another aspect of the present invention, it relates to the use of a diaminophenothiazine compound in preparing an oral formulation with a gastric retention platform, wherein the use is for treating and / or preventing avian wasting disease.

[0021] According to another aspect of the present invention, it relates to a method for treating or preventing a disease, comprising: An effective amount of a diaminophenothiazine compound in an oral formulation having a mucoadhesive gastric retention platform is administered to a non-human animal having the disease, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC).

[0022] According to another aspect of the present invention, there is provided a composition comprising a diaminophenothiazine compound, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC); and a mucoadhesive gastric retentive platform, wherein the mucoadhesive gastric retentive platform is selected from one or more of the group consisting of one or more polysaccharides, chitosan and hyaluronic acid.

[0023] Other aspects and features of the present invention will be apparent to those skilled in the art after reading the following description of specific embodiments of the present invention in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In the accompanying drawings, which are illustrated by way of non-limiting example only, embodiments of the invention comprise,

[0025] [ Figure 1 ]: An oral formulation in the form of a solution comprising a diaminophenothiazine compound and a mucoadhesive carbohydrate.

[0026] [Figure 2]: A bird before (A) and after (B) treatment for avian giant bacterium disease, (C) Post-treatment stool smear microscopy showed only 2% of the original giant bacterial pathogen load.

[0027] [Figure 3]: (A) Schematic diagram of an oral formulation comprising a diaminophenothiazine compound and a mucoadhesive carbohydrate (e.g., a mixture of a diaminophenothiazine compound and a polysaccharide as a mucoadhesive gastric retention platform), which adheres to the stomach wall; (B) shows the avian intestinal peripheral nervous system.

[0028] [ Figure 4 ]: Body weight of black palm cockatoos diagnosed with giant bacterium infection during treatment with an oral formulation of MTC and hyaluronic acid. DETAILED DESCRIPTION

[0029] Throughout this document, unless otherwise indicated to the contrary, the terms "comprising," "consisting of," "having" and similar words, are to be construed as "non-exhaustive," or in other words, meaning "including, but not limited to,".

[0030] Furthermore, throughout this document, unless the context requires otherwise, the word “include” Or variations such as “includes” or “including” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0031] Throughout the description, it is understood that the term "mucoadhesive gastric retention platform" and its plural forms may include a mucoadhesive gastric retention platform capable of retaining an effective amount of a diaminophenothiazine compound in the stomach for 20 minutes, or 1 to 3 hours or longer framework. In various embodiments, the mucoadhesive gastric retention platform may be referred to as or include a mucoadhesive, such as a carbohydrate, protein, glycoprotein, polymer, or any other mucoadhesive with sufficient interfacial force to anchor on the gastric mucosa. In various embodiments, the mucoadhesive gastric retention platform may be referred to as or include a mucoadhesive carbohydrate, because carbohydrates may provide a platform or system that allows the diaminophenothiazine compound to remain in the stomach for a longer time, thereby increasing absorption, activity and effectiveness. Other mucoadhesive gastric retention platforms may also be used, as long as they can be retained in the stomach for a longer time, so that the diaminophenothiazine compound can have increased absorption, activity and effectiveness. In various embodiments, the mucoadhesive gastric retention platform may include a system that can retain an effective amount of the diaminophenothiazine compound in the stomach for 20 minutes or more, 30 minutes or more, 50 minutes or more. In various embodiments, the mucoadhesive gastric retention platform may include a mucoadhesive gastric retention platform capable of retaining an effective amount of a diaminophenothiazine compound in the stomach for 1 hour or more, 2 hours or more, In various embodiments, the mucoadhesive gastric retention platform may increase the bioavailability of an effective amount of a diaminophenothiazine compound by more than 1.2 times, more than 1.3 times, more than 1.4 times, more than 1.6 times, more than 1.7 times, more than 1.8 times, more than 1.9 times, more than 2.0 times, more than 3.0 times, more than 4.5 times, more than 5.0 times, more than 6.5 times, more than 7.0 times, more than 8.0 times, more than 9.5 times, more than 10.0 times, more than 11.5 times, more than 12.0 times, more than 13.0 times, more than 14.0 times, more than 15.0 times, more than 16.0 times, more than 17.0 times, more than 18.0 times, more than 19.0 times, more than 20.0 times, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more or 2 times or more.

[0032] As used herein, the term "veterinary use" refers to use in all animals other than humans. In various embodiments, the non-human animal may be a vertebrate. In various embodiments, the non-human animal may be a bird.

[0033] As used herein, the term "wasting disease" refers to a wasting disease caused by an infectious agent. A disease of a non-human animal caused by a pathogen (e.g., bacteria, fungus, or virus) that results in weight loss in the non-human animal. In various embodiments, the wasting disease comprises an avian wasting disease, including but not limited to avian giant bacterium disease, avian bornavirus infection, avian paramyxovirus infection, and psittacine beak and feather disease.

[0034] As used herein, the term "treating, treat or treatment" refers to preventing or reducing further illness, consumption, infection or death of non-human animals. In various embodiments, the non-human animal may be a vertebrate. In various embodiments, the non-human animal may be a bird. In various embodiments, the treatment includes veterinary treatment. In various embodiments, it is possible to prevent or reduce further illness, consumption, infection or death of non-human animals by reducing the infectious agent (e.g., bacteria, fungi or viruses). In various embodiments, it is possible to prevent or reduce further illness, consumption, infection or death of non-human animals by reducing the presence of avian gastric yeast in fecal swabs or other samples. In various embodiments, it is possible to prevent or reduce further illness, consumption, infection or death of non-human animals by reducing the presence of Bornaviridae viruses in blood or other samples. In various embodiments, it is possible to prevent or reduce further illness, consumption, infection or death of non-human animals by reducing the presence of psittacine circovirus in blood or other samples. In various embodiments, it is possible to prevent or reduce further illness, consumption, infection or death of non-human animals by reducing the presence of avian Borna viruses. In various embodiments, preventing or reducing further illness, wasting or infection may be measured by maintaining or increasing the body weight or mass of the non-human animal. In various embodiments, preventing or reducing further illness, wasting, infection or death of a non-human animal may be achieved by reducing the presence of avian paramyxovirus.

[0035] As used herein, the term "preventing, prevent or prevention" refers to preventing or minimizing the illness, infection or death of uninfected animals that may be immunocompromised or may have been exposed to infected animals. In various embodiments, prevention may be referred to as prophylactic. In various embodiments, the non-human animal may be a vertebrate. In various embodiments, the non-human animal may be a bird. In various embodiments, the prevention includes veterinary uses for prevention. In various embodiments, a prophylactic or preventative preparation may be given to an immunocompromised non-human animal to prevent, block or minimize the possibility of infection by an infectious agent (e.g., bacteria, fungi or viruses). In various embodiments, a prophylactic or preventative preparation may be given to a non-human animal that has been exposed to an infected animal in an attempt to prevent, block or minimize the possibility of infection by an infectious agent (e.g., bacteria, fungi or viruses). In various embodiments, the possibility of preventing, blocking or minimizing the infection of a non-human animal may be achieved by preventing infection by giant yeast avian stomach. In various embodiments, the possibility of preventing, blocking or minimizing infection in non-human animals may be achieved by preventing infection with Bornaviridae viruses. In various embodiments, the possibility of preventing, blocking or minimizing infection in non-human animals may be achieved by preventing infection with psittacine circoviruses. In various embodiments, the possibility of preventing, blocking or minimizing infection in non-human animals may be achieved by preventing infection with avian Borna viruses. In various embodiments, the possibility of preventing, blocking or minimizing infection in non-human animals may be achieved by preventing infection with avian paramyxoviruses. It may be understood that the dosing regimen or frequency for prevention may be lower than the dosing regimen or frequency required for treatment. In various embodiments, the oral formulation may be administered once a week for prevention.

[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs.

[0037] According to various embodiments, an oral formulation is provided, comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC), the oral formulation being for veterinary use in treating and / or preventing a disease.

[0038] In various embodiments, the oral formulation may be prepared as a fluid, preferably a gel, a liquid or a spray. In various embodiments, the oral formulation may be prepared as a mucoadhesive solid, preferably a powder, a film or microparticles or nanoparticles. In various embodiments, the oral formulation may be prepared as a combination of one or more of a gel, a liquid, a spray, a powder, a film, microparticles and nanoparticles. In various embodiments, an oral formulation of any of the listed formulations may be added to the drinking water of the non-human animal.

[0039] In various embodiments, the formulation is controlled release, resulting in the release of the active ingredient of the diaminophenothiazine targeted to the upper gastrointestinal tract when used. In addition, the formulation has gastroretentive properties. These properties can help optimize the controlled absorption of the diaminophenothiazine compound gradually in the stomach and reduce the side effects of the drug on the lower large intestine. These properties can help reduce the frequency of administration of the oral formulation.

[0040] In various embodiments, the diaminophenothiazine compound comprises an active ingredient of a DAPTZ compound. In various embodiments, the diaminophenothiazine compound comprises methylthioninium chloride (MTC). In various embodiments, the diaminophenothiazine compound may comprise methylthioninium chloride (MTC). In various embodiments, the MTC diaminophenothiazine compound comprises 3,7-bis(dimethylamino)phenothiazin-5-ium chloride (3,7-bis(dimethylamino) phenothiazin-5-ium chloride).

[0041] In various embodiments, the diaminophenothiazine compound may include compounds similar to MTC, wherein the chloride ion may be replaced by one or more anionic counterions to achieve electrical neutrality. Examples of suitable anionic counterions may be salts, including pharmaceutically acceptable salts or halides, including -Br, -I or NO 3 In various embodiments, the diaminophenothiazine compound may include compounds similar to MTC, wherein at least one, at least two, at least three or all methyl groups may be replaced by any of the following: H, unsubstituted aliphatic C 2-6 Alkyl, substituted aliphatic C 2-6 Alkyl, unsubstituted C 3-6 Cycloalkyl, substituted C 3-6 Cycloalkyl, unsubstituted C 6-10 Carboaryl, substituted C 6-10 Carboaryl, unsubstituted C 5-10 Heteroaryl, substituted C 5-10 Heteroaryl, unsubstituted C6-10 Carboaryl-C 1-4 Alkyl, substituted C 6-10 Carboaryl-C 1-4 alkyl.

[0042] In various embodiments, the gastric retention platform may include microparticles, wherein the diaminophenothiazine compound is encapsulated in the microparticles. In various embodiments, the microparticles include poly (lactide-co-glycolide) (PLGA) microspheres, however any microparticles known in the art that can provide a slow / sustained release profile are suitable. In various embodiments, the PLGA microspheres include a polymer ratio of PLGA (50:50), PLGA (75:25) or PLGA (85:15). These ratios may be able to adjust the release profile of the diaminophenothiazine compound. In various embodiments, the microparticles are coated with a mucoadhesive, such as a carbohydrate, a protein, a glycoprotein, a polymer, or any mucoadhesive having sufficient interfacial forces to anchor the microparticles to the gastric mucosa. In various embodiments, the microparticles are coated with chitosan. In various embodiments, the microparticles are coated with hyaluronic acid.

[0043] In various embodiments, the mucoadhesive gastric retention platform may include a gastric targeting platform to ensure that the release of the active diaminophenothiazine compound occurs in the gastric lumen, where diaminophenothiazine is preferably absorbed in an acidic environment. In various embodiments, the mucoadhesive gastric retention platform may be formed from elements that dissolve at low pH, allowing any diaminophenothiazine-loaded microparticles to be embedded in the matrix to be distributed and maintained in the matrix throughout before reaching the stomach. The lower pH in the stomach then enables any released diaminophenothiazine-loaded microparticles to be better absorbed in the stomach, which can then adhere to the stomach and slowly release MTC.

[0044] In various embodiments, the mucoadhesive gastroretentive platform comprises a carbohydrate. In various embodiments, the mucoadhesive gastroretentive platform comprises one or more polysaccharides. In various embodiments, the mucoadhesive gastroretentive platform comprises one or more glucosamines. In various embodiments, the one or more polysaccharides comprise hyaluronic acid. In various embodiments, the one or more polysaccharides comprise chitosan. In various embodiments, the one or more polysaccharides comprise a combination of hyaluronic acid and chitosan. In various embodiments, the one or more glucosamines comprise hyaluronic acid. In various embodiments, the one or more glucosamines include chitosan. In various embodiments, the one or more glucosamines include a combination of hyaluronic acid and chitosan. In various embodiments, The mucoadhesive carbohydrates include one or more polysaccharides, including hyaluronic acid.

[0045] In various embodiments, the mucoadhesive gastroretentive platform may include chitosan (β(1-4) linked D-glucosamine and N-acetyl-D-glucosamine), which is formed from a polymer of the following disaccharide monomers, where n may be any number between 2 and 10,000.

[0046] In various embodiments, the mucoadhesive gastric retention platform may include hyaluronic acid, an anionic, non-sulfated glycosaminoglycan. It may also be referred to as sodium hyaluronate. It is formed from a polymer of the following disaccharide monomers, where n may be any number between 2 and 20,000.

[0047] In various embodiments, in any oral formulation listed herein, the mucoadhesive gastric retentive platform may be selected from one or more of the group consisting of one or more polysaccharides, carbohydrates, microparticles preferably coated with a mucoadhesive agent, proteins, polymers, and glycoproteins. In various embodiments, the mucoadhesive gastric retentive platform comprises a protein, such as gelatin. In various embodiments, the mucoadhesive gastric retentive platform comprises a glycoprotein. In various embodiments, the mucoadhesive gastric retentive platform comprises a carbohydrate, such as chitosan and hyaluronic acid. In various embodiments, the mucoadhesive gastric retentive platform comprises one or more polysaccharides. In various embodiments, the mucoadhesive gastric retentive platform comprises hyaluronic acid. In various embodiments, the mucoadhesive gastric retentive platform comprises chitosan. In various embodiments, the mucoadhesive gastric retentive platform comprises a combination of hyaluronic acid and chitosan. In various embodiments, the one or more polysaccharides comprise hyaluronic acid. In various embodiments, the one or more polysaccharides comprise chitosan. In various embodiments, the one or more polysaccharides comprise a combination of hyaluronic acid and chitosan.

[0048] Without being limited to any theory, the inventors speculate that hyaluronic acid and / or chitosan may form an attachment to the mucosal layer of the stomach or duodenal wall, thereby retaining the active ingredient of the diaminophenothiazine in that area for a long time. In various embodiments, carbohydrates with these speculated mucoadhesive properties may be more suitable for use in birds because the upper gastrointestinal tract of birds is very compartmentalized and has specialized mechanisms to move food through the system. Therefore, the volume of gastric juice in birds is smaller relative to the surface area of ​​the upper gastrointestinal tract than other animals (such as humans). This means that the mucoadhesive will not get stuck in the mouth or any part of the upper gastrointestinal tract of birds, allowing the mucoadhesive gastric retention platform to move freely into the stomach or duodenum, and then be able to attach to the mucosal layer of the stomach or duodenal wall there.

[0049] In various embodiments, the diaminophenothiazine compound comprises methylthioninium chloride (MTC). In various embodiments, the formulation comprises methylthioninium chloride (MTC) and a mucoadhesive gastric retention platform. In various embodiments, the formulation comprises methylthioninium chloride (MTC) and hyaluronic acid. In various embodiments, the formulation comprises methylthioninium chloride (MTC) and chitosan. In various embodiments, the formulation comprises methylthioninium chloride (MTC) and mucoadhesive carbohydrates as mucoadhesive gastric retention platforms.

[0050] In various embodiments, an effective amount of a diaminophenothiazine compound is formulated with 2 to 3 times the amount of a mucoadhesive gastric retention platform. In various embodiments, the formulation comprises 1 part of an effective amount of a diaminophenothiazine compound dissolved in a solvent and 2 to 3 parts of a mucoadhesive gastric retention platform. In various embodiments, the solvent is sterile water. In various embodiments, other solvents (e.g., buffer solutions, saline solutions, juice solutions) may also be used. In various embodiments, 20 to 50 mg of a diaminophenothiazine compound and 60 to 100 mg of a mucoadhesive gastric retention platform are dissolved in 1 liter of solvent. In various embodiments, 25 to 45 mg of a diaminophenothiazine compound and 65 to 95 mg of a mucoadhesive gastric retention platform are dissolved in 1 liter of solvent. In various embodiments, 30 mg of a diaminophenothiazine compound and 70 to 90 mg of a mucoadhesive gastric retention platform are dissolved in 1 liter of solvent. In various embodiments, 30 mg of an effective amount of a diaminophenothiazine compound and 80 mg of a mucoadhesive gastric retention platform are dissolved in 1 liter of solvent. In various embodiments, the oral formulation consists only of a diaminophenothiazine compound and a mucoadhesive carbohydrate, both of which are dissolved in the solvent. This will ensure that the active ingredient is delivered to the low pH environment of the stomach and that no substance interferes with the active ingredient or the mucoadhesive carbohydrate to achieve this goal.

[0051] In various embodiments, the formulation further includes other accompanying active ingredients, additives, excipients, diluents, binders, lubricants, disintegrants, fillers, stabilizers, surfactants, antioxidants or combinations thereof. In various embodiments, the other accompanying active ingredients may include any known antibiotics, anti-inflammatory drugs, antifungal drugs or antiviral drugs.

[0052] According to various embodiments, an oral formulation is provided, comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform, the oral formulation being useful for treating and / or preventing a disease, wherein the disease includes a disease associated with intestinal peripheral neuropathy. In various embodiments, the infectious agent (e.g., avian Borna virus) causes dysfunction of the peripheral nerves of the avian forestomach-gastrointestinal tract (see Figure 3BIn various embodiments, the infectious agent (e.g., avian paramyxovirus) may also infect Figure 3B The avian forestomach described in the fore stomach - peripheral nerves of the gastrointestinal tract. Due to neuropathy, the motility and secretory functions of the gastrointestinal system can be impaired, ultimately leading to nutrient malabsorption, starvation, wasting and death. Perforation of gastrointestinal structures can occur due to severe distension caused by the stagnation and accumulation of ingested food particles in the gastrointestinal tract. Therefore, intestinal peripheral neuropathy leads to and may be referred to as a wasting disease, such as avian wasting disease. In various embodiments, the oral formulation includes any of the formulations described above. In various embodiments, the disease includes a wasting disease. In various embodiments, an oral formulation comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform is for veterinary use for the treatment and / or prevention of diseases associated with intestinal peripheral neuropathy.

[0053] In various embodiments, the formulation is prepared for daily administration. In various embodiments, the formulation is prepared for weekly administration. In various embodiments, the formulation for treating a disease is prepared for daily administration. In various embodiments, the formulation for preventing a disease is prepared for weekly administration.

[0054] In various embodiments, oral formulations comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform may be used to treat and / or prevent diseases caused by infectious agents (e.g., bacteria, fungi, or viruses) that affect the stomach or upper gastrointestinal tract. In various embodiments, the disease is a wasting disease. In various embodiments, oral formulations comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform are veterinary uses for the treatment and / or prevention of veterinary wasting diseases. In various embodiments, oral formulations comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform may be used to treat and / or prevent esophageal-gastric perforation and ulcers. In various embodiments, the esophageal-gastric perforation and ulcers may be caused by fungi. In various embodiments, the esophageal-gastric perforation and ulcers may be caused by giant yeast avian stomach.

[0055] According to various embodiments, an oral formulation is provided comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform for use in treating and / or preventing avian wasting disease. In various embodiments, the oral formulation comprises any of the formulations described above.

[0056] In various embodiments, the formulations for treating and / or preventing avian wasting disease are prepared for daily administration. In various embodiments, the formulations for treating and / or preventing avian wasting disease are prepared for weekly administration. In various embodiments, the formulations for treating avian wasting disease are prepared for daily administration. In various embodiments, the formulations for preventing avian wasting disease are prepared for weekly administration. In various embodiments, the formulations for preventing avian wasting disease are prepared for monthly administration.

[0057] In various embodiments, it is understood that the term "avian wasting disease" and its plural forms include diseases that cause weight loss (and in some cases muscle atrophy or indigestion) in birds. In various embodiments, avian wasting diseases include diseases associated with avian intestinal peripheral neuropathy, avian giant bacterial disease, avian paramyxovirus infection, avian bornavirus infection, avian bornavirus, or psittacine beak and feather disease.

[0058] In various embodiments, the avian wasting disease is selected from avian giant bacterium disease, avian paramyxovirus infection, avian borna virus infection, psittacine beak and feather disease, and a disease associated with intestinal peripheral neuropathy.

[0059] In various embodiments, the formulations are prepared for oral administration to birds, preferably by gavage using a syringe, although pipettes, eyedroppers, tube feeding and other suitable gavage methods may be used.

[0060] In various embodiments, the disease is a gastrointestinal infection, including esophageal-gastric perforation and ulcers caused by an infectious agent. In various embodiments, the wasting disease includes a gastrointestinal infection with esophageal-gastric perforation and ulcers caused by an infectious agent.

[0061] According to various embodiments, an oral formulation is provided, comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform, the oral formulation being used to treat and / or prevent esophageal-gastric perforation and ulcers. In various embodiments, the oral formulation comprises any formulation described above. In various embodiments, the esophageal-gastric perforation and ulcers may be caused by fungi. In various embodiments, the gastric perforation and ulcers may be caused by Giant Bacillus avium.

[0062] According to various embodiments, there is provided a use of a diaminophenothiazine compound in the preparation of an oral formulation having a mucoadhesive gastric retention platform for the treatment and / or prevention of a disease. In various embodiments, the oral formulation comprises any formulation described above. In various embodiments, the disease is a disease associated with intestinal peripheral neuropathy. In various embodiments, the disease is avian wasting disease. In various embodiments, the disease is esophageal-gastric perforation and ulcer.

[0063] In various embodiments, the avian wasting disease is selected from avian giant bacterium disease, avian paramyxovirus infection, avian borna virus infection, psittacine beak and feather disease, and a disease associated with intestinal peripheral neuropathy.

[0064] In various embodiments, the formulation is prepared for oral administration to a bird, preferably by gavage using a syringe, although a pipette, dropper, tube feeding, and other suitable gavage methods may be used.

[0065] According to various embodiments, a method of treating or preventing a disease is provided, comprising administering to a non-human animal suffering from the disease an effective amount of a diaminophenothiazine compound in an oral formulation having a mucoadhesive gastric retention platform, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC).

[0066] In various embodiments, the disease is avian wasting disease. In various embodiments, the disease is a disease associated with intestinal peripheral neuropathy. In various embodiments, the disease is a gastrointestinal infection, including esophageal-gastric perforation and ulcers of the upper gastrointestinal tract caused by infectious agents.

[0067] In various embodiments, the non-human animal may be a vertebrate, and the disease is associated with intestinal peripheral neuropathy. In various embodiments, the non-human animal may be a vertebrate, and The disease is a wasting disease. In various embodiments, the non-human animal may be a vertebrate and the disease is associated with esophageal-gastric perforation and / or ulcer. In various embodiments, the non-human animal may be a bird and the disease is associated with intestinal peripheral neuropathy. In various embodiments, the non-human animal may be a bird and the disease is an avian wasting disease. In various embodiments, the disease causes esophageal-gastric perforation and / or ulcer.

[0068] In various embodiments, the diaminophenothiazine compound used in the method comprises methylthioninium chloride (MTC). In various embodiments, the formulation used in the method comprises methylthioninium chloride (MTC) and a mucoadhesive gastric retention platform. In various embodiments, the formulation used in the method comprises methylthioninium chloride (MTC) and hyaluronic acid. In various embodiments, The formulation used in the method includes methylthioninium chloride (MTC) and chitosan.

[0069] In various embodiments, an effective amount of a diaminophenothiazine compound and 2 to 3 times the amount of a mucoadhesive gastric retention platform are formulated into an oral formulation for administration. In various embodiments, the oral formulation used in the method comprises 1 part of an effective amount of a diaminophenothiazine compound and 2 to 3 parts of a mucoadhesive gastric retention platform dissolved in a solvent. In various embodiments, the solvent used in the method may include a buffer solution, a saline solution, a juice solution, an aqueous solution, or any other solution known in the art suitable for oral administration. In various embodiments, the solvent used in the method is sterile water. In various embodiments, the oral formulation used in the method comprises 20 to 50 mg of a diaminophenothiazine compound and 60 to 100 mg of a mucoadhesive gastric retention platform dissolved in 1 liter of solvent. In various embodiments, the oral formulation used in the method comprises 25 to 45 mg of a diaminophenothiazine compound and 65 to 95 mg of a mucoadhesive gastric retention platform dissolved in 1 liter of solvent. In various embodiments, the oral formulation used in the method comprises 30 mg of a diaminophenothiazine compound and 70 to 90 mg of a mucoadhesive gastric retention platform dissolved in 1 liter of solvent. In various embodiments, the oral formulation used in the method comprises 30 mg of a diaminophenothiazine compound and 80 mg of a mucoadhesive gastric retention platform dissolved in 1 liter of solvent.

[0070] In various embodiments, an effective amount of a diaminophenothiazine compound in an oral formulation having a mucoadhesive gastric retention platform for use in a method of treatment is administered daily. In various embodiments, the oral formulation comprises any of the formulations described above. In various embodiments, less than 5 μg of the diaminophenothiazine compound is administered daily per kilogram of non-human animal body weight. In various embodiments, less than 4.5 μg of the diaminophenothiazine compound is administered daily per kilogram of non-human animal body weight. In various embodiments, less than 4 μg of the diaminophenothiazine compound is administered daily per kilogram of non-human animal body weight.

[0071] In various embodiments, an effective amount of a diaminophenothiazine compound in an oral formulation with a mucoadhesive gastric retention platform for use in a method of prevention is administered weekly. In various embodiments, the oral formulation comprises any of the formulations described above. In various embodiments, less than 5 μg of the diaminophenothiazine compound is administered per kilogram of non-human animal body weight per week. In various embodiments, less than 4.5 μg of the diaminophenothiazine compound is administered per kilogram of non-human animal body weight per week. In various embodiments, less than 4 μg of the diaminophenothiazine compound is administered per kilogram of non-human animal body weight per week.

[0072] In various embodiments, the method of treating avian wasting disease is used to treat avian giant bacterium disease.

[0073] In various embodiments, the method further comprises determining the presence of M. avium in birds with avian wasting disease or avian giant bacterium disease after receiving daily doses of the oral formulation for at least one month. In various embodiments, the presence of M. avium is determined using a fecal smear under a microscope.

[0074] In various embodiments, the methods of treating avian wasting disease are used to treat Borna virus infection in birds.

[0075] In various embodiments, the method further comprises determining the presence of Borna virus in birds with avian wasting disease or Borna virus infection after receiving daily doses of the oral formulation for at least one month. In various embodiments, the presence of Borna virus is determined using PCR of cloacal smears.

[0076] In various embodiments, the method of treating an avian wasting disease is used to treat psittacine beak and feather disease.

[0077] In various embodiments, the method further comprises determining the presence of psittacine circovirus in a bird suffering from avian wasting disease or psittacine beak and feather disease after receiving daily doses of the oral formulation for at least one month. In various embodiments, the presence of circovirus is determined using PCR in a blood test.

[0078] In various embodiments, the methods of treating avian wasting disease are used to treat Borna virus infection in birds.

[0079] In various embodiments, the method further comprises determining the presence of avian Borna virus in a bird suffering from avian wasting disease or avian Borna virus infection after receiving daily doses of the oral formulation for at least one month. In various embodiments, the presence of avian Borna virus is determined using PCR of cloacal smears.

[0080] In various embodiments, the method is used to treat gastric perforation and ulcers. The method is used to treat giant bacterium disease in birds.

[0081] In various embodiments, the method further comprises determining the presence of E. avium in a bird suffering from avian wasting disease after receiving daily doses of the oral formulation for at least one month. In various embodiments, microscopic stool smears are used to determine the presence or absence of M. ornithogalum.

[0082] In various embodiments, the method is used to treat gastric perforations and ulcers.

[0083] In various embodiments, the mucoadhesive gastroretentive platform used in the method comprises a carbohydrate, wherein the carbohydrate is selected from one or more of the group consisting of one or more polysaccharides, glycoproteins, chitosan, and hyaluronic acid. In various embodiments, the mucoadhesive gastroretentive platform used in the method comprises any of the mucoadhesive gastroretentive platform embodiments listed above.

[0084] When an oral formulation comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform is used, the active ingredient MTC can be retained in the gastric fundus or gastric body for a longer time, thereby being retained in the acidic environment of the gastric fluid for a longer time, so that the active diaminophenothiazine compound can be better absorbed. For example, in various embodiments, as described in FIG3 , in a mixture 10 of a diaminophenothiazine compound and a mucoadhesive gastric retention platform, the mucoadhesive gastric retention platform enables the mixture 10 to adhere to the stomach wall 2 of the gastric body portion 6, thereby enhancing absorption. In various other embodiments, this enables the diaminophenothiazine compound to be absorbed in gastric fluid 12 having a lower pH, and the formulation 10 can be retained in the stomach 12 (whether near the gastric fundus 4 or in the gastric body 6) for a longer time, thereby enhancing absorption.

[0085] According to various embodiments, a composition is provided comprising a diaminophenothiazine compound, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC); and a mucoadhesive gastroretentive platform, wherein the mucoadhesive gastroretentive platform is selected from one or more of the group consisting of one or more polysaccharides, chitosan, and hyaluronic acid.

[0086] In various embodiments, the composition further comprises other accompanying ingredients, additives, excipients, diluents, binders, lubricants, disintegrants, fillers, stabilizers, surfactants, antioxidants or combinations thereof. In various embodiments, the compound is formulated for oral delivery, preferably for oral delivery to birds or avian species.

[0087] Example

[0088] Example 1: Treatment of avian megalobacteriosis

[0089] A black palm cockatoo was diagnosed by a veterinarian with a giant bacterial infection. The bird was emaciated, had a distended crop, and had liquid feces containing undigested food. This resulted in a weight loss of 800 mg from its pre-illness weight. Due to its poor condition, the bird was placed on palliative supplement management (papaya seeds, juice, formula, and supplements).

[0090] The birds were treated with a daily dose of 0.05 ml of an oral formulation (0.003% MTC and 0.008% hyaluronic acid dissolved in sterile water) for 54 days.

[0091] [Table 1]: Condition of Black Palm Cockatoo during treatment

[0092] The same treatment was subsequently successfully replicated in other bird species (see [ Figure 4 ]).

[0093] Example 2: Treatment of Borna virus infection in birds

[0094] A Moluccan Cockatoo presented with regurgitation, loss of appetite, indigestion, and lack of energy. A cloacal smear tested positive for avian borna virus (ABV) by PCR.

[0095] The birds were treated with a daily dose of 0.15 ml of an oral formulation (0.003% MTC and 0.008% hyaluronic acid dissolved in sterile water) every morning for 43 days.

[0096] [Table 2]: Status of Moluccan Cockatoos during treatment

[0097] The same treatment was subsequently successfully repeated in other bird species (data not shown).

[0098] Example 3: Treatment of Psittacine Beak and Feather Disease

[0099] A Moluccan Cockatoo presented with regurgitation, loss of appetite, indigestion and lack of energy. The bird was diagnosed as positive for psittacine circovirus (PCV), the virus that causes psittacine beak and feather disease, by PCR testing of a blood sample.

[0100] The birds were treated with a daily dose of 0.15 ml of an oral formulation (0.003% MTC and 0.008% hyaluronic acid dissolved in sterile water) every morning for 43 days.

[0101] [Table 3]: Status of Moluccan Cockatoos during treatment

[0102] The same treatment was subsequently successfully repeated in other bird species (data not shown).

[0103] A trial has been initiated with wild teals, and it has been reported that once PCV infection spreads among a flock of birds, These teals may die by the hundreds or thousands. Because of the large number of birds and the mix of potentially sick birds and possibly healthy birds living with them, the trial will be conducted in three separate flocks using three different dosing schedules: the first is daily dosing; the second is dosing every 3 days; and the third is dosing once a week. At the same time, an untreated flock will be observed.

[0104] Example 4: Prevention of avian giant bacterium disease

[0105] The black palm cockatoo diagnosed by a veterinarian as having a giant bacteria infection in Example 1 was co-housed with another cockatoo in the same cage. The feces of the infected bird contained a large number of giant bacteria, which meant that the co-housed birds had a high probability of being exposed to the infection and becoming infected with M. avium. It was initially recommended that the co-housed birds should be culled to prevent further spread of the giant bacteria infection. As an alternative, the birds were given a weekly dose of 0.05 ml of an oral formulation (0.003% MTC and 0.008% hyaluronic acid, dissolved in sterile water) until the estimated incubation period of the pathogen was over and the source of infection was eliminated.

[0106] The mixed birds showed no signs of infection and remained healthy thanks to weekly preventative medications.

[0107] [Table 4]: Status of mixed-housed cockatoos during preventive treatment

[0108] The same treatment was subsequently successfully repeated in other mixed bird species (data not shown).

[0109] It should be further understood by those skilled in the art that variations and combinations of the above-mentioned features, rather than substitutions or replacements, may be combined to form further embodiments, falling within the intended scope of the present invention.

[0110] As will be appreciated by those skilled in the art, each embodiment may be used in combination with other embodiments or some embodiments.

Claims

1. An oral formulation comprising a diaminophenothiazine compound and a mucoadhesive gastric retention platform, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC), the oral formulation being for veterinary use in the treatment and / or prevention of a disease.

2. The preparation for use according to claim 1, characterized in that An effective amount of a diaminophenothiazine compound is formulated with 2 to 3 times the amount of a mucoadhesive gastric retention platform.

3. The preparation for use according to claim 1 or 2, characterized in that The mucoadhesive gastric retentive platform comprises a carbohydrate.

4. The preparation for use according to any one of claims 1 or 2, characterized in that The mucoadhesive gastric retentive platform comprises one or more polysaccharides.

5. The preparation for use according to any one of claims 1 or 2, characterized in that The mucoadhesive gastric retentive platform comprises hyaluronic acid.

6. The preparation for use according to any one of claims 1 or 2, characterized in that The mucoadhesive gastroretentive platform comprises chitosan.

7. The preparation for use according to any one of claims 1 or 2, characterized in that The mucoadhesive gastric retentive platform is selected from one or more of the group consisting of microspheres coated with a mucoadhesive agent, carbohydrates, proteins, glycoproteins, polymers, one or more polysaccharides, chitosan, and hyaluronic acid.

8. The preparation for use according to any one of claims 1 to 7, characterized in that The oral formulation further comprises other accompanying active ingredients, additives, excipients, diluents, binders, lubricants, disintegrants, fillers, stabilizers, surfactants, antioxidants or combinations thereof.

9. The preparation for use according to any one of claims 1 to 8, characterized in that Such diseases include diseases associated with intestinal peripheral neuropathy.

10. The preparation for use according to any one of claims 1 to 9, characterized in that Such diseases include avian wasting disease.

11. The preparation for use according to claim 10, characterized in that The avian wasting disease is selected from the group consisting of avian giant bacterium disease, avian paramyxovirus infection, avian borna virus infection, and psittacine beak and feather disease.

12. The preparation for use according to claim 10 or 11, characterized in that The formulation is administered orally to the bird.

13. The preparation for use according to any one of claims 1 to 9, characterized in that The disease is a gastrointestinal infection including esophageal-gastric perforation or ulceration of the upper gastrointestinal tract caused by an infectious agent.

14. Use of a diaminophenothiazine compound in the preparation of an oral preparation, characterized in that: The oral formulation comprises a methylthioninium chloride (MTC) compound and a mucoadhesive gastric retention platform, the use of which is for treating and / or preventing diseases, and the use of which is for treating and / or preventing avian wasting disease.

15. The use according to claim 14, characterized in that An effective amount of MTC is formulated with 2 to 3 times the amount of the mucoadhesive gastric retentive platform.

16. The use according to claim 14 or 15, characterized in that The mucoadhesive gastric retentive platform comprises a carbohydrate.

17. The use according to any one of claims 14 or 15, characterized in that The mucoadhesive gastric retentive platform comprises one or more polysaccharides.

18. The use according to any one of claims 14 or 15, characterized in that The mucoadhesive gastric retentive platform comprises hyaluronic acid.

19. The use according to any one of claims 14 or 15, characterized in that The mucoadhesive gastroretentive platform comprises chitosan.

20. The use according to any one of claims 14 or 15, characterized in that The mucoadhesive gastric retentive platform is selected from one or more of the group consisting of microspheres coated with a mucoadhesive agent, carbohydrates, proteins, glycoproteins, polymers, one or more polysaccharides, chitosan, and hyaluronic acid.

21. The use according to any one of claims 14 to 20, characterized in that The oral formulation further comprises other accompanying active ingredients, additives, excipients, diluents, binders, lubricants, disintegrants, fillers, stabilizers, surfactants, antioxidants or combinations thereof.

22. The use according to any one of claims 14 to 21, characterized in that The avian wasting disease is selected from the group consisting of avian giant bacterium disease, avian paramyxovirus infection, avian borna virus infection, psittacine beak and feather disease, and diseases associated with intestinal peripheral neuropathy.

23. The use according to any one of claims 14 to 22, characterized in that The oral formulation is administered through the oral cavity of the bird.

24. The use according to any one of claims 14 to 21, characterized in that The disease is a gastrointestinal infection including esophageal-gastric perforation or ulceration of the upper gastrointestinal tract caused by an infectious agent.

25. A method for treating or preventing a disease, comprising: An effective amount of a diaminophenothiazine compound in an oral formulation having a mucoadhesive gastric retention platform is administered to a non-human animal having a veterinary disease, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC).

26. The method according to claim 25, characterized in that The method comprises formulating the effective amount of the diaminophenothiazine compound with 2 to 3 times the amount of a mucoadhesive gastric retention platform.

27. The method according to claim 25, characterized in that The mucoadhesive gastric retentive platform is selected from one or more of the group consisting of carbohydrates, one or more polysaccharides, chitosan, and hyaluronic acid.

28. The method according to claim 25, characterized in that An effective amount of a diaminophenothiazine compound in the oral formulation having a mucoadhesive gastric retention platform is administered daily.

29. The method according to claim 25, characterized in that The disease is an avian wasting disease, and the avian wasting disease includes avian giant bacterium disease.

30. The method according to claim 29, characterized in that The method further comprises determining the presence of Macrorhabdus ornithogaster in a bird suffering from avian macrobacterial disease after receiving daily doses of the oral formulation for at least one month.

31. The method according to claim 25, characterized in that The disease is avian wasting disease and / or a disease associated with enteric peripheral neuropathy, wherein the disease associated with enteric peripheral neuropathy includes avian Borna virus infection.

32. The method according to claim 31, characterized in that The method further comprises determining the presence of bornavirus in a bird suffering from a bornavirus infection after receiving daily doses of the oral formulation for at least one month.

33. The method according to claim 25, characterized in that The disease is an avian wasting disease, which includes psittacine beak and feather disease.

34. The method according to claim 33, characterized in that The method further comprises determining the presence of circovirus in the bird suffering from psittacine beak and feather disease after receiving daily doses of the oral formulation for at least one month.

35. The method according to claim 25, characterized in that An effective amount of a diaminophenothiazine compound in an oral formulation having a mucoadhesive gastric retention platform is administered weekly.

36. A composition comprising a diaminophenothiazine compound, wherein the diaminophenothiazine compound comprises methylthioninium chloride (MTC); and a mucoadhesive gastroretentive platform, wherein the mucoadhesive gastroretentive platform is selected from one or more of the group consisting of one or more polysaccharides, chitosan, and hyaluronic acid.

37. The composition according to claim 35, characterized in that The composition further comprises other accompanying ingredients, additives, excipients, diluents, binders, lubricants, disintegrants, fillers, stabilizers, surfactants, antioxidants or combinations thereof.

38. The composition according to claim 35 or 36, characterized in that The composition is formulated for oral delivery.

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